The molecular genetic analysis of pathologic conditions of the human uterus, including endometrial carcinoma, uterine sarcoma and uterine leiomyoma (fibroids) are under study. Significant progress has been made in defining the relevant oncogenes and tumor suppressor genes involved in endometrial carcinoma. Analysis of endometrial carcinomas with the replication error phenotype (RER+) has been associated with mutation in genes that predispose individuals to HNPCC (heredity non polyposis colorectal cancer). Endo- metrial cancer and cell lines not associated with HNPCC have been identi- fied with RER+ phenotype. The defective genes are homologs of DNA mismatch repair genes previously identified in yeast and bacteria. Studies involving these cell lines have helped to define the biochemical role of these genes of DNA mismatch repair. Reintroduction of the wild-type gene into mutant cell lines has shown the direct association of the gene mutation with biochemical and genetic phenotypes. These phenotypes include sensitivity to alkylating agents such as MNNG, restoration of mismatch repair activity and the RER+ phenotype. Some particular mutants of the hPMS2 gene may be dominant in their ability to affect these phenotypes. Studies of the RER+ phenotype in uterine and ovarian sarcomas have indicated that a subset of these highly lethal neoplasms may involve defective DNA repair pathways. We have also analyzed breast tumors from HNPCC kindreds and found that approximately half have the RER+ phenotype and these have no wildtype gene product for the inherited mutant gene. We conclude from this data that a percentage of breast cancers in these kindreds are the result of the inherited mutation and thus breast cancer can be induced as part of the HNPCC tumor spectrum. Data involving novel loci in uterine leiomyoma and in the highly lethal leiomyosarcoma have indicated a common region of allele loss on chromosome 7q22 in 30% of leiomyoma and greater than 60% of leiomyosarcoma.